Process for the asymmetric oxidation of organic compounds with peroxides in the presence of a chiral acid catalyst

ABSTRACT

The present invention relates to a process for the asymmetric oxidation of nucleophilic organic compounds, particularly metal-free, with peroxide compounds in the presence of a chiral Brønsted acid catalyst. In one detail, the present invention relates to a process for enantioselective sulfoxidation of thiocompounds with peroxide compounds in the presence of a chiral imidodiphosphate catalyst. In another detail, the present invention relates to a process for enantioselective sulfoxidation of thiocompounds with peroxide compounds in the presence of a chiral phosphoric acid catalyst.

This application is a 371 of PCT/EP2013/050190, filed Jan. 8, 2013,which claims foreign priority benefit under 35 U.S.C. § 119 of theEuropean Patent Application Nos. 12150663.8, filed Jan. 10, 2012, and12158469.2, filed Mar. 7, 2012, the disclosures of which areincorporated herein by reference.

The present invention relates to a process for the asymmetric oxidationof nucleophilic organic compounds, particularly metal-free, withperoxide compounds in the presence of a chiral Brønsted acid catalyst.Said process is distinct from known reactions which require anelectrophilic organic compound for a reaction with a peroxide compoundin the presence of a chiral Brønsted acid catalyst (Angew. Chem. Int.Ed. 2010, 49, 6589-6591; Angew. Chem. Int. Ed. 2008, 47, 8112-8115). Thepresent invention exploits peroxide compounds as direct electrophilicsources of oxygen atom, while in the prior art peroxide compounds areexploited as nucleophiles.

In one detail, the present invention relates to a process forenantioselective sulfoxidation of thiocompounds with peroxide compoundsin the presence of a chiral imidodiphosphate catalyst. In anotherdetail, the present invention relates to a process for enantioselectivesulfoxidation of thiocompounds with peroxide compounds in the presenceof a chiral phosphoric acid catalyst.

Asymmetric oxidations of organic compounds, in particular thoseincluding oxygen atom transfer to the substrate, are highly valuabletransformations for accessing chiral molecules. Both, enzymes andnumerous artificial catalysts employ metals to facilitate these types ofreactions.

Hydrogen peroxide is next to oxygen the most attractive oxidant, withthe waste produced after the reaction being only water. It is producedon a million ton scale each year, and widely available in the form ofsafe aqueous solutions. Unsurprisingly, significant efforts have beenundertaken to utilize H₂O₂ for oxidations in organic chemistry. In metalcatalysis it is used as a terminal oxidant with actual oxidizingintermediates being, for example, metal-oxo and metal-peroxo species.

Chiral sulfoxides are widely used as intermediates, auxiliaries, andligands in modern organic synthesis, and they are also a common andperhaps underappreciated substructure of many biologically activemolecules and pharmaceuticals such as Omeprazole, Esomeprazole andModafinil (R. Bentley, Chem. Soc. Rev. 2005, 34, 609-623; J. Legros, J.R. Dehli, C. Bolm, Adv. Synth. Catal. 2005, 347, 19-31). Of the methodsfor the synthesis of enantioenriched sulfoxides (e.g. resolution,substrate or reagent-controlled synthesis), the enantioselectivecatalytic oxidation of sulfides is the most efficient andstraightforward approach. Since the first catalytic system was reportedin 1984 by Kagan (P. Pitchen, E. Duñach, M. N. Deshmukh, H. B. Kagan, J.Am. Chem. Soc. 1984, 106, 8188-8193) and Modena (F. DiFuria, G. Modena,R. Seraglia, Synthesis 1984, 325-326), using modified Sharplessepoxidation catalysts, several elegant metal-based enantioselectivesulfoxidation reactions of sulfides have been developed during the lastthree decades.

However, such metal-based systems usually suffer from some limitationslike metal contamination, over-oxidation, a limited substrate scope etc.In contrast to the significant progress in the metal catalysis, thedevelopment of organocatalytic methods is still in its infancy, althoughorganocatalysis has experienced an explosive progress and expansionduring the last decade.

Among metal-free methods, high enantioselectivity has been achieved byusing chiral imines or oxaziridiniums, but these transformations requirestoichiometric amounts of the chiral reagents and the correspondingcatalytic systems are relatively less efficient. Considering theimportance of optically pure sulfoxides in synthetic and medicinalchemistry, a general, metal-free, and highly enantioselective catalyticsulfoxidation reaction of sulfides is highly desirable.

Thus, the inventors have developed a novel and metal-free method for theenantioselective oxidation of sulfides such as thioethers. Though it isquite difficult to activate simple thioethers via covalent or H-bondingactivation, which are two most common activation models inorganocatalysis, due to the lack of a site or a functional group toestablish an efficient interaction between the organic catalysts and thesulfides, the inventors have found out that a viable approach was givenby the activation of oxidants and that an asymmetric version of thesulfoxidation reaction was achieved by using chiral Brønsted acids likebinol-derived phosphoric acids or imidodiphosphates in combination withperoxide compounds like hydrogen peroxide or alkylhydroperoxide.

BRIEF DESCRIPTION OF THE DRAWING

The invention will now be described with reference to the drawing,wherein:

FIG. 1 is a schematic showing activation of the peroxide moiety bychiral Brønsted acids.

The inventors found out that peroxide moiety could be activated bybifunctional chiral Brønsted acids through formation of two hydrogenbonds as shown in FIG. 1.

The present invention is therefore directed to a process for preparingsulfoxides by enantioselectively oxidizing thiocompounds with hydrogenperoxide or alkyl hydroperoxide in the presence of a Brønsted acidcatalyst, such as chiral imidodiphosphates or phosphoric acids, forexample, a binol-derived phosphoric acid, as represented in thefollowing reaction scheme:

In a broader scope, the invention is directed to oxidizing a compoundX^(s)R^(X) _(n) with a peroxide compound ROOH in the presence of achiral imidodiphosphate catalyst having the general formula (I) below toobtain X^(s)(—O)R^(X) _(n)— including the representations of R^(x)_(n)X^(s+)—O⁻ and R^(x) _(n)X^(s)═O— and R^(p)OH,

wherein:

-   -   X^(s) can be selected from S, Se, P or N,    -   R^(X) can be the same or different on X and may be selected from        —NR^(Y) ₂, —SR^(Y), —OR^(Y), —OSiR^(Y) ₃, C₁ to C₂₀ straight        chain, branched chain or cyclic aliphatic hydrocarbons,        optionally having one or more unsaturated bonds such as        C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl or C₂-C₂₀-alkinyl,        C₃-C₈-heterocycloalkyl or C₆ to C₂₀ aromatic hydrocarbon and        partially arene-hydrogenated forms such as aryl,        aryl-(C₁-C₆)-alkyl, heteroaryl-(C₁-C₆)-alkyl, each hydrocarbon        optionally being substituted by one or more groups selected from        C₁ to C₂₀ straight chain, branched chain or cyclic aliphatic        hydrocarbons, optionally having one or more unsaturated bonds        such as C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl or C₂-C₂₀-alkinyl,        C₃-C₈-heterocycloalkyl or C₆ to C₂₀ aromatic hydrocarbon and        partially arene-hydrogenated forms such as aryl,        aryl-(C₁-C₆)-alkyl, heteroaryl-(C₁-C₆)-alkyl or        heterosubstituents,    -   n is 2 when X^(s) is S or Se, and n is 3 when X^(s) is P or N,    -   R^(p) and R^(Y) may be independently selected from C₁ to C₂₀        straight chain, branched chain or cyclic aliphatic hydrocarbons,        optionally having one or more unsaturated bonds such as        C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl or C₂-C₂₀-alkinyl,        C₃-C₈-heterocycloalkyl or C₆ to C₂₀ aromatic hydrocarbon and        partially arene-hydrogenated forms such as aryl,        aryl-(C₁-C₆)-alkyl, heteroaryl-(C₁-C₆)-alkyl, each hydrocarbon        optionally being substituted by one or more groups selected from        C₁ to C₂₀ straight chain, branched chain or cyclic aliphatic        hydrocarbons, optionally having one or more unsaturated bonds        such as C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl or C₂-C₂₀-alkinyl,        C₃-C₈-heterocycloalkyl or C₆ to C₂₀ aromatic hydrocarbon and        partially arene-hydrogenated forms such as aryl,        aryl-(C₁-C₆)-alkyl, heteroaryl-(C₁-C₆)-alkyl or        heterosubstituents.

In principle X^(s)R^(X) _(n) can be any S, Se, P or N compound which canbe oxidized to give an S⁺—O⁻, Se⁺—O⁻, P⁺—O⁻ or N⁺—O⁻ compound as a finalproduct or as an intermediate which is further reacted in the reaction.

In the simplest form, the peroxide compound is hydrogen peroxide, butaliphatic or aromatic hydroperoxides, aliphatic or aromaticpercarboxylic acids or mixtures thereof might be used as well.

In a further embodiment, the present invention is directed to a processfor oxidizing an alkylene compound to an epoxy compound and optionally,further hydrolyzing said epoxy compound to a hydroxyl compound or,depending on the substituent on the alkylene unit, to an alpha-hydroxy-carbonyl-compound.

In said reaction scheme, R^(s1) to R^(s4) may have the meaning as givenbefore for R^(X). In principle any double bond which can be oxidized togive an epoxide, as a final product or as an intermediate which isfurther reacted in the reaction.

In a still further embodiment, the present invention is directed to aprocess for oxidizing an alpha-hydrogen-carbonyl-compound to analpha-hydroxy-carbonyl-compound.

In said reaction scheme, R^(s1) to R^(s3) may have the meaning as givenbefore for R^(X) and R^(p) may have the meaning as given before. Inprinciple any alpha-hydrogen-carbonyl-compound which can be oxidized togive an alpha-hydroxy-carbonyl-compound, as a final product or as anintermediate which is further reacted in the reaction. In addition(CO)R^(s3) could be replaced by another electron-withdrawing groupshaving a tautomerizable double bond adjacent to the CH-site, such as—NO₂, —CN.

In embodiments of the inventive processes, the present invention makesuse of chiral imidodiphosphates and derivatives thereof having thegeneral formula (I), which have been described in EP12150663.8, asfollows:

wherein:X and Y may be, independently from each other, the same or different andrepresent O, S, Se and NR^(N),Z¹ to Z⁴ may be, independently from each other, the same or differentand represent O, S and NR^(N),n stands for 0 or preferably 1,W may be substituent being capable of forming a covalent or ionic bondwith the imidodiphosphate moiety,R¹ to R⁴ may be, independently from each other, the same or differentand may be each an aliphatic, heteroaliphatic, aromatic orheteroaromatic group, each optionally being further substituted by oneor more heterosubstituents, aliphatic, heteroaliphatic, aromatic orheteroaromatic groups whereby R¹ and R² are forming a ring system withZ¹ and Z² and R³ and R⁴ are forming a ring system with Z³ and Z⁴,respectively, andR^(N) may be selected from hydrogen, C₁ to C₂₀ straight chain, branchedchain or cyclic aliphatic hydrocarbons, optionally having one or moreunsaturated bonds such as C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl orC₂-C₂₀-alkinyl, C₃-C₈-heterocycloalkyl or C₆ to C₂₀ aromatic hydrocarbonand partially arene-hydrogenated forms such as aryl, aryl-(C₁-C₆)-alkyl,heteroaryl-(C₁-C₆)-alkyl, each hydrocarbon optionally being substitutedby one or more groups selected from C₁ to C₂₀ straight chain, branchedchain or cyclic aliphatic hydrocarbons, optionally having one or moreunsaturated bonds such as C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl orC₂-C₂₀-alkinyl, C₃-C₈-heterocycloalkyl or C₆ to C₂₀ aromatic hydrocarbonand partially arene-hydrogenated forms such as aryl, aryl-(C₁-C₆)-alkyl,heteroaryl-(C₁-C₆)-alkyl or heterosubstituents,including its tautomeric and ionic forms, and derivatives thereof.

In the following, it is to be understood that the above formula (I)comprises its tautomeric forms as represented by the formulae (Ia) or(Ib)

wherein X, Y, Z¹ to Z⁴, n, W, R¹ to R⁴ and R^(N) have the meaning asdefined above. In the following, it is to be understood that any of theformulae (II), (III), (IV) and (V) below comprises its respectivetautomeric forms as represented by formula (Ia) or formula (Ib).

In the present application, the expression “imidodiphosphates” is to beunderstood to comprise derivatives thereof, wherein one or more of theoxygen atoms of the imidodiphosphate moiety is replaced by S, Se, NR^(N)as defined above.

In the above formula (I) and the derived formulae below, it is to beunderstood that any tautomeric form of the inventive chiralimidodiphosphates as well as any charged form thereof including anyanionic form is to be comprised by the representation of said formula.It is also to be understood that imidodiphosphates could possessinherent chirality even if all of the groups R¹ to R⁴ are achiralgroups.

In the above formulae (I), R¹ to R⁴ may be selected each from C₁ to C₂₀straight chain, branched chain or cyclic aliphatic hydrocarbons,optionally having one or more unsaturated bonds such as C₁-C₂₀-alkyl,C₂-C₂₀-alkenyl or C₂-C₂₀-alkinyl, C₃-C₈-heterocycloalkyl or C₆ to C₂₀aromatic hydrocarbon and partially arene-hydrogenated forms such asaryl, aryl-(C₁-C₆)-alkyl, heteroaryl-(C₁-C₆)-alkyl, each hydrocarbonoptionally being substituted by one or more groups selected from C₁ toC₂₀ straight chain, branched chain or cyclic aliphatic hydrocarbons,optionally having one or more unsaturated bonds such as C₁-C₂₀-alkyl,C₂-C₂₀-alkenyl or C₂-C₂₀-alkinyl, or C₆ to C₂₀ aromatic hydrocarbon andpartially arene-hydrogenated forms such as aryl, aryl-(C₁-C₆)-alkyl,heteroaryl-(C₁-C₆)-alkyl or heterosubstituents.

In the above formula (I), W is a substituent being capable of forming acovalent or ionic bond with the imidodiphosphate moiety such ashydrogen, —OH, halogen, a metal such as Li, Na, K, Rb, Cs, Be, Mg, Ca,Sr, Ba, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Mo, Ru, Rh, Pd,Ag, W, Re, Os, Ir, Pt, Au, Al, Pb, La, Sm, Eu, Yb, U, or a cationicorganic group as exemplified in Scheme 2 below, R^(w) or a substitutedsilicon such as —SiR^(I)R^(II)R^(III), wherein R^(w), R^(I), R^(II) andR^(III) may be same or different and each stand for hydrogen, halogen,C₁ to C₂₀ straight chain, branched chain or cyclic aliphatichydrocarbons, optionally having one or more unsaturated bonds such asC₁-C₂₀-alkyl, C₂-C₂₀-alkenyl or C₂-C₂₀-alkinyl, C₃-C₈-heterocycloalkylor C₆ to C₂₀ aromatic hydrocarbon and partially arene-hydrogenated formssuch as aryl, aryl-(C₁-C₆)-alkyl, heteroaryl-(C₁-C₆)-alkyl, eachhydrocarbon optionally being substituted by one or more groups selectedfrom C₁ to C₂₀ straight chain, branched chain or cyclic aliphatichydrocarbons, optionally having one or more unsaturated bonds such asC₁-C₂₀-alkyl, C₂-C₂₀-alkenyl or C₂-C₂₀-alkinyl, C₃-C₈-heterocycloalkylor C₆ to C₂₀ aromatic hydrocarbon and partially arene-hydrogenated formssuch as aryl, aryl-(C₁-C₆)-alkyl, heteroaryl-(C₁-C₆)-alkyl or aheterosubstituent.

The expression “partially arene-hydrogenated forms thereof” is to beunderstood that in case that the aromatic structure comprises more thanone aromatic cycle such as for naphthalene, at least one aromatic cycle,one aromatic cycle remaining, might be partially or fully hydrogenated.

The anionic form may be complemented by any cation for forming an ionpair.

In one embodiment of the above formulae (I), Z¹ to Z⁴ represent O, n is1 and the other definitions are as given before for formula (I), asrepresented by formula (II):

In such formulae (I) and (II), the moiety

might be a five to ten-membered ring structure of (R¹, R², Z¹, Z² and—PY—) or (R³, R⁴, Z³, Z⁴ and —PX—), respectively.

In one embodiment of the compounds of formula (II), X and Y represent Oand the other definitions are as given before for formulae (I), asrepresented by formula (III):

In such formula (III), at least one of (R¹ and R²) and (R³ and R⁴) mayform a ring structure derived from a bridged aromatic structure such asbiphenyl optionally substituted, BINOL, TADDOL, VAPOL, SPINOL,1,1′-binaphthalene, 1,1′-bianthracene, 1,1-biphenanthrene, as well asthe partially arene-hydrogenated forms such as 8H-BINOL, each of saidrings systems optionally being substituted by one or more substituentsselected from heterosubstituents, C₁ to C₂₀ straight chain, branchedchain or cyclic aliphatic hydrocarbons, optionally having one or moreunsaturated bonds such as C₁-C₂₀-alkyl, C₂-C₂₀-alkenyl orC₂-C₂₀-alkinyl, C₃-C₈-heterocycloalkyl or C₆ to C₂₀ aromatic hydrocarbonsuch as aryl, aryl-(C₁-C₆)-alkyl, heteroaryl-(C₁-C₆)-alkyl, eachhydrocarbon optionally being substituted by one or moreheterosubstituents. In such formula (III), the ring structure formed by(R¹ and R²) or (R³ and R⁴) may be the same or different.

Examples of said compound having the formula (III) and prepared by theinventors are shown below:

In a further embodiment, the compounds of formula (I) may be representedby formula (IV):

In said formula (IV), the substituent R may be the same or different oneach position and may each stand for hydrogen, a heterosubstituent, C₁to C₂₀ straight chain, branched chain or cyclic aliphatic hydrocarbons,optionally having one or more unsaturated bonds such as C₁-C₂₀-alkyl,C₂-C₂₀-alkenyl or C₂-C₂₀-alkinyl, C₃-C₈-heterocycloalkyl or C₆ to C₂₀aromatic hydrocarbon and partially arene-hydrogenated forms such asaryl, aryl-(C₁-C₆)-alkyl, heteroaryl-(C₁-C₆)-alkyl, each hydrocarbonoptionally being substituted by one or more groups selected from C₁ toC₂₀ straight chain, branched chain or cyclic aliphatic hydrocarbons,optionally having one or more unsaturated bonds such as C₁-C₂₀-alkyl,C₂-C₂₀-alkenyl or C₂-C₂₀-alkinyl, C₃-C₈-heterocycloalkyl or C₆ to C₂₀aromatic hydrocarbon and partially arene-hydrogenated forms such asaryl, aryl-(C₁-C₆)-alkyl, heteroaryl-(C₁-C₆)-alkyl or aheterosubstituent.

In said formula (IV), W is defined as given before for formula (I).

The substituents on the ring structure proximal to the —Z—P— bond, suchas the —O—P-bond, are preferably bulky groups and may be selected fromthe definitions for R^(N) or heterosubstituents.

In the inventive processes, the chiral imidodiphosphates having thegeneral formula (II), (III) or (IV) are preferably used.

Basically, any chiral groups are possible as chiral groups for theinventive compounds. If the other group in each case is not chiral, thegroups R¹ to R⁴ are any organic group which may be saturated orunsaturated, linear, cyclic or heterocyclic, aromatic and/orheteroaromatic.

Examples of said compound having the formula (IV) and prepared by theinventors are shown below:

In organic synthesis, particularly in the synthesis of pharmaceuticalactive compounds, chiral compounds are frequently used as catalysts inorder to obtain the desired product in a high enantiomeric purity ordiastereomeric purity.

It has been found that the compounds according to the invention are wellsuited as catalysts for enantioselective synthesis. Here, they functionas chiral Brønsted acids or the conjugated bases thereof as chiralanions in enantioselective catalyses directed by counterions.

The following definitions for the individual substituents/groups applyequally as follows.

A heterosubstituent as defined according to the invention can beselected from OH, F, CI, Br, I, CN, NO₂, SO₃H, a monohalogenomethylgroup, a dihalogenomethyl group, a trihalogenomethyl group, CF(CF₃)₂,SF₅, amine bound through N atom, —O-alkyl (alkoxy), —O-aryl, —O—SiR^(S)₃, —S—R^(S), —S(O)—R^(S), —S(O)₂—R^(S), —COOH, CO₂—R^(S), -amide, boundthrough C or N atom, formyl group, C(O)—R^(S), COOM, where M may be ametal such as Na or K. R^(S) ₃ may be, independently from each other,the same or different and may be each an aliphatic, heteroaliphatic,aromatic or heteroaromatic group, each optionally being furthersubstituted by one or more heterosubstituents, aliphatic,heteroaliphatic, aromatic or heteroaromatic groups.

Aliphatic hydrocarbons including alkyl, alkenyl and alkinyl may comprisestraight-chain, branched and cyclic hydrocarbons.

Heteroaliphatic is a hydrocarbon including alkyl, alkenyl and alkinylwhich may comprise straight-chain, branched and cyclic hydrocarbons withone or more carbon atoms substituted with a heteroatom.

In more detail, C₁-C₂₀-Alkyl can be straight chain or branched and has1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20carbon atoms. Alkyl might be C₁-C₆-alkyl, in particular methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, likewisepentyl, 1-, 2- or 3-methylpropyl, 1,1-, 1,2- or 2,2-dimethylpropyl,1-ethylpropyl, hexyl, 1-, 2, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-,2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl. Substituted alkyl groups are trifluoromethyl,pentafluoroethyl and 1,1,1-trifluoroethyl.

Cycloalkyl might be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl orcycloheptyl. Alkenyl might be C₂-C₂₀ alkenyl. Alkinyl might be C₂-C₂₀alkinyl.

Said unsaturated alkenyl- or alkinyl groups can be used for linking theinventive compounds to a carrier such as a polymer to serve for animmobilized catalyst.

Halogen is F, Cl, Br or I.

Alkoxy is preferably C₂-C₁₀ alkoxy such as methoxy, ethoxy, propoxy,tert-butoxy etc.

C₃-C₈-Heterocycloalkyl having one or more heteroatoms selected fromamong N, O and S is preferably 2,3-dihydro-2-, -3-, -4- or -5-furyl,2,5-dihydro-2-, -3-, -4- or -5-furyl, tetrahydro-2- or -3-furyl,1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-,-3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl,1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl,2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or-4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl,1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or-4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3-or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or-8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or-8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or8-3,4-dihydro-2H-benzo-1,4-oxazinyl.

Optionally substituted means unsubstituted or monosubstituted,disubstituted, trisubstituted, tetrasubstituted, pentasubstituted, oreven further substituted for each hydrogen on the hydrocarbon.

Aryl might be phenyl, naphthyl or biphenyl.

Arylalkyl might be benzyl.

Heteroaryl having one or more heteroatoms selected from among N, O and Sis preferably 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-,2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl,3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or5-isothia-zolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, alsopreferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or-5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl,1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl,1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-Indolyl, 4- or5-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-,5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-,4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5-or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-1,4-oxazinyl, alsopreferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl,2,1,3-benzothiadiazol-4- or -5-yl or 2,1,3-benzoxadiazol-5-yl.

In a preferred embodiment of the present invention as for example shownin formula (IV), at least one of R proximal to the —O—P— bond is nothydrogen and may be selected from among methyl, ethyl, isopropyl,cyclohexyl, cyclopentyl, phenyl, 2,4,6-triisopropylphenyl,2,4,6-triethylphenyl, 2,6-diethylphenyl, 2,6-diethylphenyl,2-isopropylphenyl, 5-methyl-2-isopropylphenyl, mesityl, 9-phenanthryl,9-anthracenyl, ferrocenyl, N-(perfluorophenyl)acetamide,N-(4-chlorophenyl)acetamide, N-(naphthalen-1-yl)acetamide,N-benzhydrylacetamide, N-(2,6-diisopropylphenyl)acetamide,1-anthracenyl, corannulene, porphyrin, 1-naphthyl, 2-naphthyl,4-biphenyl, 3,5-(trifluoromethyl)phenyl, 2,6-dimethylphenyl, tert-butyl,tris-methylsilyl, tert-butydimethylsilyl, phenyldimethylsilyl,methyldiphenylsilyl, tris-mesitylsilyl, tris-phenylsilyl, 4-nitrophenyland 2,6-methyl-4-butylphenyl, trifluoromethyl, unbranched (linear) andbranched (C₁-C₁₂)-perfluoroalkyls, 3,4,5-trifluorophenyl,1,3-bis(perfluoropropan-2-yl)phenyl, 1,3-bis(perfluorobutyl)phenyland/or pentafluorophenyl and also chloride, iodide, fluoride, COOH,B(OH)₂, B(alkyl)₂, B(O-alkyl)₂, B(pinacol), BF₃X where X=Na or K, OTf.The other groups are preferably hydrogen.

The compounds according to the invention can be converted in processsteps which are well known per se to those skilled in the art intoorganic salts, metal salts or metal complexes. In one possibleembodiment, the imidodiphosphates are reacted with an appropriate metalsalt, for example with the carbonate of the appropriate metal. Examplesof organic salts, metal salts and metal complexes are shown in thefollowing Scheme 1 for formula (V):

In Scheme 1, any metals or organic cations, e.g. tertiary ammonium ions,can be represented by M. Even though the compounds are shown as salts inscheme 1, the precise structure with metals is not known; they can alsohave the structure of metal complexes. The formulation metal salts ormetal complexes is therefore used for the purposes of the presentinvention. The metal compounds are not restricted to particular metalcompounds or complexes. Suitable metal compounds are derived from Li,Na, K, Rb, Cs, Be, Mg, Ca, Sr, Ba, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu,Zn, Y, Zr, Mo, Ru, Rh, Pd, Ag, W, Re, Os, Ir, Pt, Au, Al, Pb, La, Sm,Eu, Yb, U.

In other embodiments of the inventive processes, the present inventionmakes use of chiral acids and derivatives thereof as catalysts which areknown in the state of art such as those disclosed in:

-   EP 1623971.-   Hoffmann, S., Seayad, A. M. & List, B. Angew. Chem. Int. Ed. 44,    7424-7427 (2005).-   Xu, F. et al. J. Org. Chem. 75, 8677-8680 (2010).-   Čorić, I., Müller, S. & List, B. J. Am. Chem. Soc. 132, 17370-17373    (2010).-   Nakashima, D. & Yamamoto, H. J. Am. Chem. Soc. 128, 9626-9627    (2006).-   Akiyama, T., Itoh, J., Yokota, K. & Fuchibe, K. Angew. Chem. Int.    Ed. 43, 1566-1568 (2004).-   Uraguchi, D. & Terada, M. J. Am. Chem. Soc. 126, 5356-5357 (2004).-   Storer, R. I., Carrera, D. E., Ni, Y. & MacMillan, D. W. C. J. Am.    Chem. Soc. 128, 84-86 (2006).-   Rowland, G. B. et al. J. Am. Chem. Soc. 127, 15696-15697 (2005).-   Akiyama, T., Saitoh, Y., Morita, H. & Fuchibe, K. Adv. Synth. Catal.    347, 1523-1526 (2005).-   Müller, S., Webber, M. J. & List, B. J. Am. Chem. Soc., 133,    18534-18537 (2011).-   García-García, P., Lay, F., García-García, P., Rabalakos, C. &    List, B. Angew. Chem. Int. Ed. 48, 4363-4366 (2009).-   Vellalath, S., Čorić, I. & List, B. Angew. Chem. Int. Ed. 49,    9749-9752 (2010).

Such chiral acid catalyst to be used for the asymmetric oxidationwithout the need of an intermediate activation reaction making use of anactivation reagent such as a coupling agent like carbodiimide here canbe selected from chiral phosphoric acids, sulfonic acids, carboxylicacids, bisulfonimides, triflyl phosphoramides, phosphinyl phosphoramidesand derivatives thereof preferably on the basis of a aromatic structureas exemplified above for formula (III) such as BINOL, TADDOL, VAPOL,SPINOL, as well as the partially arene-hydrogenated forms thereof suchas 8H-BINOL, and comprises a reactive site represented by a formula[—(P,S,C)═O][(—NHR^(E), —OH]— wherein R^(E) has the meaning of anelectron-withdrawing group, as represented exemplarily as follows:

In said formulae, R can have the meaning as given above for R in formula(IV) and its preferred embodiments.

The inventive process is usually carried out in conventional organicsolvent such as hydrocarbon solvents such as hexanes, pentane,methylcyclohexane, heptane, isooctane preferably cyclohexane,halogenated solvents such as chloroform, dichloromethane,dichloroethane, chlorobenzene, fluorobenzene, preferably carbontetrachloride, aromatic solvents such as benzene, toluene, substitutedbenzenes, xylenes, ethers such as tetrahydrofuran,methyltetrahydrofuran, tert-butylmethyl ether, diisopropyl ether,diethyl ether, dioxane, esters such as ethyl acetate, isopropyl acetate,or any other solvent or mixtures thereof that do not negativelyinfluence the reaction,

The inventive process can be carried out under an atmosphere of gas thatdoes not negatively influence the reaction, preferably in a protectiveatmosphere such as nitrogen, argon, or in air, preferably in a closedcontainer.

The process temperature is usually from −78° C. to 100° C., preferably−20 to 25° C. Addition of a drying agent such as MgSO₄, Na₂SO₄, ormolecular sieves to the reaction mixture to partially remove water, isnot necessary but can have beneficial effect on the reaction rate,enabling lower catalyst loadings, reduced reaction time, and possiblyincrease in enantioselectivity.

Though each peroxide might be generally used for the inventive oxidationmethod, the reaction conditions might be optimized by the choice of theperoxide compound, in particular with respect to the reaction rate andenantioselectivity.

The invention is further illustrated by the following Examples.

Experimental Part

In the following Examples, the general method for oxidizingthiocompounds using hydrogen peroxide is carried out in an organicsolvent such as hexane or CCl₄ in the presence of an exemplary catalystsuch as imidodiphosphate catalyst as exemplified for compounds 5a and5b. The catalyst preparation is carried out in line with the procedureas illustrated in EP12150663.8 in detail.

With the addition of MgSO₄ to remove water, the reaction time can besignificantly shortened to 2 hours, and only 1.05 equivalents ofhydrogen peroxides are required (entry 3). Both cyclohexane and CCl₄ canbe employed as the solvent, giving the same results (entries 3-4).Moreover, the catalyst loading can be lowered to 1 mol %, withouterosion of enantioselectivity, though needing a longer reaction time(entry 5). Further lowering the catalyst loading to 0.1 mol % can alsogive a high enantioselectivity of 95:5 er (entry 6).

TABLE Test of bisphosphonimide catalysts.^(a) Conversion Sulfonyl EntryAcid t (h) (%)^(b) compound (%)^(b) e.r.^(c) 1 5a 24 90 n.d. 92:8 2 5b24 80 n.d. 99:1 3^(d) 5b 2 >99   n.d. 99:1 4^(d,e) 5b 2 >99   n.d. 99:15^(d,f) 5b 10 >99   n.d. 98.5:1.5 6^(d,g) 5b 72   75% n.d. 95:5 ^(a)0.1mmol scale, 2 mol % acid, aq. H₂O₂ (1.10 eq), in cyclohexane (2 mL),r.t. ^(b)Determined by GCMS, n.d. = not detected. ^(c)Determined bychiral HPLC analysis. ^(d)With MgSO₄, aq. H₂O₂ (1.05 eq). ^(e)In CCl₄.^(f)1 mol % catalyst. ^(g)0.1 mol % catalyst.

As it can be seen from the above table, a perfect enantioselectivity wasobserved with acid 5b. Having the optimized reaction conditionsestablished, the inventors next examined the reaction scope with aseries of representative substrates. As revealed in following Table, aremarkable broad range of aryl methyl sulfides can be converted to thecorresponding sulfoxides in high yields with excellent enantio- andchemoselectivity, regardless the electronic nature (from —OMe to —NO₂)and position (o-, m-, p-) of the substituents. Substrates with a bulkyalkyl group can also be oxidized with high enantioselectivity, yet asmall amount of sulfone (5-9%) was observed. Remarkably, high yields andoptical purity were also obtained in the cases of simple alkylthioethers. To the best of the inventor's knowledge, the levels ofenantioselectivity are the highest so far in organocatalytic systems,and the generality of this novel organocatalytic sulfoxidation is alsounprecedented,^([8]) even when compared to the metal-catalyzedreactions.

TABLE Substrate scope of asymmetric sulfoxidation.

Product (Rs¹ and Rs² as generally defined above and Yield Entry beingidentifiable from below) (%)^(a) e.r.^(b)

 1 X = H (2a) 98% 99.5:0.5  2 4-MeO (2b) 96% 97.5:2.5  3 4-Me (2c) 98%98:2  4 4-Cl (2d) 91% 98.5:1.5  5 3-Cl (2e) 95% 99.5:0.5  6 2-Cl (2f)99% 99:1  7 4-CN (2g) 92% 97.5:2.5  8 4-NO₂ (2h) 95% 99.5:0.5  9

  (2i) 98% 99:1

10^(d) R = Et (2j) 90% 95:5 11^(e) i-Pr (2k) 89% 92.5:7.5 12^(f)

  (2l) 96% 97:3 13^(f,g)

  (2m) 96% 95.5:4.5 ^(a)Isolated yields on 0.1-0.4 mmol scales.^(b)Determined by HPLC analysis on a chiral phase. ^(d)5% sulfoneobserved by ¹H NMR. ^(e)9% sulfone. ^(f)In CCl₄, at 0° C. ^(g)2%sulfone.

The practical synthetic relevance of the inventive method wasdemonstrated with the enantioselective synthesis of Sulindac, which isan efficient non-steroidal anti-inflammatory drug and recently appliedalso to the cancer treatment. The oxidation of the Sulindac sulfide wasperformed under standard reaction conditions, followed by the hydrolysisof the ester group, giving Sulindac in 98% yield and 99:1 er.

In summary, a novel and highly efficient organocatalytic oxidationsystem, chiral Brønsted acid/aq. H₂O₂, has been developed, andsuccessfully applied to the sulfoxidation of thioethers with excellentenantioselectivity and chemoselectivity. The observed generality andhigh levels of enantioselectivity are unprecedented in the area oforganocatalytic sulfoxidation reactions.

General Procedure for the Asymmetric Oxidation of Sulfides in thePresence of a Imidodiphosphate Catalyst

To a solution of phenyl methyl sulfide (24 mg, 24 μL, 0.2 mmol, 1.0equiv) and the acid catalyst 5b (6 mg, 4.0 μmol, 0.02 equiv) in 2 mL ofcyclohexane was added MgSO₄ (90 mg) and aq. H₂O₂ (35%, 18 μL, 0.21 mmol,1.05 equiv) in one portion. The resulting mixture was stirred vigorouslyat room temperature until no more conversion was observed by TLC or GCMS(2 h). Purification by column chromatography on silica gel (EtOAc) gavethe desired sulfoxide as a white solid. The ratios of sulfoxide/sulfonewere determined by ¹H-NMR analysis of the crude product. The opticalpurity of the product was determined by HPLC analysis (Daicel ChiralcelOB-H, heptane/isopropanol 70:30, 0.5 ml/min, 254 nm). The absoluteconfiguration of the sulfoxide was determined by comparison of the HPLCretention times and the optical rotation with the literature values.

The following compounds were produced in line with the general procedureas detailed before:

C₇H₈OS (140.20 g/mol), white solid, purified by column chromatography onsilica gel (EtOAc), 98% yield; ¹H NMR (300 MHz, CDCl₃): δ 2.73 (s, 3H,CH₃), 7.50-7.55 (m, 3H, ArH), 7.66 (d, J=7.8 Hz, 2H, ArH); ¹³C NMR (75MHz, CDCl₃): δ 44.0, 123.5, 129.4, 131.0, 145.7 (d); MS (EI): m/z 140(M⁺); HPLC: The optical purity (er=99.5:0.5) was determined by HPLC(DAICEL OB-H, heptane/isopropanol 70:30, flow rate: 0.5 mL/min, 254 nm,t_(r)=13.4 and 21.8 min).

C₈H₁₀O₂S (170.23 g/mol), white solid, purified by column chromatographyon silica gel (EtOAc/hexanes, 1:1), 96% yield; ¹H NMR (500 MHz, CDCl₃):δ 2.70 (s, 3H, CH₃), 3.86 (s, 3H, OCH₃), 7.03 (dt, J=8.8, 2.0 Hz, 2H,ArH), 7.60 (dt, J=8.8, 2.0 Hz, 2H, ArH); ¹³C NMR (125 MHz, CDCl₃): δ44.0, 55.5, 114.8, 125.5, 136.6, 162.0; MS (EI): m/z 170 (M⁺); HPLC: Theoptical purity (er=97.5:2.5) was determined by HPLC (DAICEL OB-H,heptane/isopropanol 50:50, flow rate: 0.5 mL/min, 254 nm, t_(r)=11.7 and19.0 min).

C₈H₁₀OS (154.23 g/mol), white solid, purified by column chromatographyon silica gel (EtOAc/hexanes, 1:1), 98% yield; ¹H NMR (500 MHz, CDCl₃):δ 2.41 (s, 3H, Ar—CH₃), 2.71 (s, 3H, CH₃), 7.33 (d, J=8.2 Hz, 2H, ArH),7.54 (d, J=8.2 Hz, 2H, ArH); ¹³C NMR (125 MHz, CDCl₃): δ 21.4, 44.0,123.6, 130.1, 141.5, 142.5; MS (EI): m/z 154 (M⁺); HPLC: The opticalpurity (er=98:2) was determined by HPLC (DAICEL OB-H,heptane/isopropanol 50:50, flow rate: 0.5 mL/min, 220 nm, t_(r)=9.5 and15.2 min).

C₇H₇CIOS (174.65 g/mol); white solid, purified by column chromatographyon silica gel (EtOAc), 97% yield; ¹H NMR (500 MHz, CDCl₃): δ 2.73 (s,3H, CH₃), 7.52 (d, J=8.5 Hz, 2H, ArH), 7.60 (d, J=8.5 Hz, 2H, ArH); ¹³CNMR (125 MHz, CDCl₃): δ 44.0, 125.0, 129.7, 137.3, 144.2; MS (EI): m/z174 (M⁺); HPLC: The optical purity (er=98.5:1.5) was determined by HPLC(DAICEL OB-H, heptane/isopropanol 50:50, flow rate: 0.5 mL/min, 254 nm,t_(r)=9.9 and 12.5 min).

C₇H₇CIOS (174.65 g/mol); white solid, purified by column chromatographyon silica gel (EtOAc), 95% yield; ¹H NMR (500 MHz, CDCl₃): δ 2.75 (s,3H, CH₃), 7.47-7.51 (m, 3H, ArH), 7.67 (d, J=0.8 Hz, 1H, ArH); ¹³C NMR(125 MHz, CDCl₃): δ 44.0, 121.6, 123.6, 130.6, 131.2, 135.7, 147.8; MS(EI): m/z 174 (M⁺); HPLC: The optical purity (er=99.5:0.5) wasdetermined by HPLC (DAICEL OB-H, heptane/isopropanol 50:50, flow rate:0.5 mL/min, 254 nm, t_(r)=10.4 and 12.7 min).

C₇H₇CIOS (174.65 g/mol); white solid, purified by column chromatographyon silica gel (EtOAc/hexanes, 1:1), 99% yield; ¹H NMR (500 MHz, CDCl₃):δ 2.83 (s, 3H, CH₃), 7.40 (dd, J=7.9, 1.1 Hz, 1H, ArH), 7.45 (td, J=7.6,1.4 Hz, 1H, ArH), 7.55 (td, J=7.5, 1.1 Hz, 1H, ArH), 7.96 (dd, J=7.8,1.4 Hz, 1H, ArH); ¹³C NMR (125 MHz, CDCl₃): δ 41.8, 125.3, 128.2, 129.8,132.0, 143.7; MS (EI): m/z 174 (M⁺); HPLC: The optical purity (er=99:1)was determined by HPLC (DAICEL OB-H, heptane/isopropanol 50:50, flowrate: 0.5 mL/min, 254 nm, t_(r)=10.1 and 14.0 min).

C₈H₇NOS (165.21 g/mol), white solid, purified by column chromatographyon silica gel (EtOAc), 92% yield; ¹H NMR (500 MHz, CDCl₃): δ 2.77 (s,3H, CH₃), 7.78 (dt, J=8.6, 2.0 Hz, 2H, ArH), 7.84 (dt, J=8.6, 2.0 Hz,2H, ArH); ¹³C NMR (125 MHz, CDCl₃): δ 43.8, 114.8, 117.7, 124.3, 133.0,151.5; MS (EI): m/z 165 (M⁺); HPLC: The optical purity (er=97.5:2.5) wasdetermined by HPLC (DAICEL OB-H, heptane/isopropanol 50:50, flow rate:0.5 mL/min, 254 nm, t_(r)=21.5 and 26.7 min).

C₇H₇NO₃S (185.20 g/mol), white solid, purified by column chromatographyon silica gel (EtOAc), 95% yield; ¹H NMR (500 MHz, CDCl₃): δ 2.80 (s,3H, CH₃), 7.84 (dt, J=8.7, 1.9 Hz, 2H, ArH), 7.85 (dt, J=8.7, 1.9 Hz,2H, ArH); ¹³C NMR (125 MHz, CDCl₃): δ 43.9, 124.5, 124.7, 149.5, 153.3;MS (EI): m/z 185 (M⁺); HPLC: The optical purity (er=99.5:0.5) wasdetermined by HPLC (DAICEL OB-H, heptane/isopropanol 50:50, flow rate:0.5 mL/min, 254 nm, t_(r)=24.7 and 28.4 min).

C₁₁H₁₀OS (190.26 g/mol), white solid, purified by column chromatographyon silica gel (EtOAc), 98% yield; ¹H NMR (500 MHz, CDCl₃): δ 2.80 (s,3H, CH₃), 7.59-7.62 (m, 3H, ArH), 7.90-8.00 (m, 3H, ArH), 8.22 (d, J=1.5Hz, 1H, ArH); ¹³C NMR (125 MHz, CDCl₃): δ 43.8, 119.4, 124.1, 127.4,127.8, 128.1, 128.5, 129.6, 132.9, 134.4, 142.7; MS (EI): m/z 190 (M⁺);HPLC: The optical purity (er=99:1) was determined by HPLC (DAICEL OB-H,heptane/isopropanol 50:50, flow rate: 0.5 mL/min, 254 nm, t_(r)=11.4 and14.0 min).

C₈H₁₀OS (154.23 g/mol); white solid, purified by column chromatographyon silica gel (EtOAc), 90% yield; ¹H NMR (500 MHz, CDCl₃): δ 1.19 (t,J=7.4 Hz, 3H, CH₃), 2.76 (m, 1H, CH₂), 2.90 (m, 1H, CH₂), 7.47-7.54 (m,3H, ArH), 7.60-7.62 (m, 2H, ArH); ¹³C NMR (125 MHz, CDCl₃): δ 5.9, 50.2,124.1, 129.1, 130.9, 143.3; MS (EI): m/z 154 (M⁺); HPLC: The opticalpurity (er=95:5) was determined by HPLC (DAICEL OB-H,heptane/isopropanol x, flow rate: 0.5 mL/min, 254 nm, t_(r)=9.4 and 14.8min).

C₉H₁₂OS (168.26 g/mol), colorless oil, purified by column chromatographyon silica gel (EtOAc/hexanes, 1:1), 89% yield; ¹H NMR (500 MHz, CDCl₃):δ 1.14 (d, J=6.9 Hz, 3H, CH₃), 1.23 (d, J=6.9 Hz, 3H, CH₃), 2.84 (m, 1H,CH), 7.50 (m, 3H, ArH), 7.60 (m, 2H, ArH); ¹³C NMR (125 MHz, CDCl₃): δ14.0, 15.9, 54.5, 125.0, 128.9, 131.0, 141.7; MS (EI): m/z 168 (M⁺);HPLC: The optical purity (er=92.5:7.5) was determined by HPLC (DAICELOB-H, heptane/isopropanol 50:50, flow rate: 0.5 mL/min, 254 nm,t_(r)=8.6 and 11.5 min).

C₇H₁₄OS (146.25 g/mol); white solid, purified by column chromatographyon silica gel (EtOAc), 96% yield; ¹H NMR (500 MHz, CDCl₃): δ 1.25-1.46(m, 5H, CH₂), 1.71-1.74 (m, 1H, CH₂), 1.87-1.95 (m, 3H, CH₂), 2.14-2.17(m, 1H, CH₂), 2.49-2.55 (m, 4H, SCH₃); ¹³C NMR (125 MHz, CDCl₃): δ 24.9,25.2, 25.4, 25.5, 26.0, 35.2, 60.9; HPLC: MS (EI): m/z 146 (M⁺); HPLC:The optical purity (er=97:3) was determined by HPLC (DAICEL OB-H,heptane/isopropanol 90:10, flow rate: 0.5 mL/min, 220 nm, t_(r)=8.6 and11.5 min).

C₁₃H₂₈OS (232.43 g/mol); white solid, purified by column chromatographyon silica gel (EtOAc), 96% yield; ¹H NMR (500 MHz, CDCl₃): δ 0.88 (t,J=6.9 Hz, 3H, CH₃), 1.26-1.35 (m, 16H, CH₂), 1.39-1.52 (m, 2H, CH₂),1.74-1.77 (m, 2H, CH₂), 2.60 (s, 3H, SCH₃), 2.68 (m, 1H, SCH₂), 2.78 (m,1H, SCH₂); ¹³C NMR (125 MHz, CDCl₃): δ 14.1, 22.6, 22.7, 28.8, 29.19,29.25, 29.34, 29.36, 29.5, 29.6, 31.9, 38.2, 54.6; MS (EI): m/z 232(M⁺); HPLC: The optical purity (er=95.5:4.5) was determined by HPLC(DAICEL OB-H, heptane/isopropanol 98:2, flow rate: 0.5 mL/min, 220 nm,t_(r)=20.4 and 22.7 min).

Sulindac methyl ester, C₂₁H₁₉FO₃S (370.44 g/mol); white solid, purifiedby column chromatography on silica gel (EtOAc), 96% yield; ¹H NMR (500MHz, CDCl₃): δ 2.13 (s, 3H, CH₃), 2.73 (s, 3H, CH₃), 3.49 (s, 2H, CH₂),3.63 (s, 3H, CH₃), 6.48 (dt, J=8.5 and 2.0 Hz, 1H, CH), 6.80 (dd, J=8.5and 2.0 Hz, 1H, 7.06-7.08 (m, 2H, 7.59 (d, J=8.0 Hz, 2H, 7.64 (d, J=8.0Hz, 2H, CH); ¹³C NMR (125 MHz, CDCl₃): δ 10.4, 31.5, 43.8, 52.2, 106.1,110.7, 123.6, 123.7, 128.1, 129.4, 130.2, 131.7, 138.1, 139.6, 141.5,145.4, 146.6, 162.3, 164.2, 170.6; MS (EI): m/z 370 (M^(l)); HPLC: Theoptical purity (er=99:1) was determined by HPLC (DAICEL AD-3,heptane/isopropanol 90:10, flow rate: 1 mL/min, 254 nm, t_(r)=13.1 and14.2 min).

Asymmetric Oxidation of Sulfides in the Presence of a Phosphate Catalyst

In the following Examples, the inventors describe the use of chiralphosphoric acids, such as (S)-STRIP as catalysts using alkylhydroperoxides. The inventors have found that the size of the alkylgroup on the hydroperoxide oxidant had a positive effect on theenantioselectivity. For substrate in entry 1 in Table below tert-butylhydroperoxide gave e.r. 87:13, and hydrogen peroxide 58:42.

TABLE Substrate scope of phosphoric acid catalyzed asymmetricsulfoxidation.

Entry Sulfide Yield e.r.

1 X = H 93% 91:9 2 4-MeO 93:7 3 4-Me 92% 94:6 4 4-Cl 88% 93:7 5 3-Cl 88%93:7 6 2-Cl 88%  90:10 7 4-NO₂ 95%  90:10

8 R = i-Pr 92% 93:7 9 R = t-Bu 88% 95:5

Reaction scope was investigated under the optimized reaction conditions.As shown in the Table above, the substrate scope is quite general,various sulfides, electron-rich or poor can all be converted intodesired sulfoxides in high chemical yields and highenantioselectivities. Remarkably, bulky groups are also tolerated quitewell, and even higher enantioselectivity was observed with substrateslike phenyl tertbutyl sulfide (entry 9). To the best of inventorsknowledge, 95:5 er is the best results so far and even enzymes failed tooxidize this difficult substrate with high enantioselectivity.

A synthetic application of this novel organocatalytic method was carriedout in the preparation of a Sulindac analogue. Under optimizedconditions, sulfide 3 was converted into sulfoxide 4 in 98% yield and95:5 er.

The invention claimed is:
 1. A process for the asymmetric oxidation ofan organic compound by electrophilic addition of a peroxide compound,said process comprising reacting the organic compound with at least oneperoxide compound R^(p)—OOH in the presence of a chiral catalyst;wherein the at least one peroxide compound is activated in favor of saidreacting by hydrogen bonding of the at least one peroxide compound tosaid chiral catalyst; wherein said chiral catalyst is selected from thegroup consisting of chiral compounds (a) and (b), wherein the chiralcompounds (a) are selected from the group consisting of chiralimidodiphosphates, and the chiral compounds (b) are selected from thegroup consisting of phosphoric acids, sulfonic acids, bisulfonimides,triflyl phosphoramides, and phosphinyl phosphoramides, said chiralcompounds (b) comprising a catalytically active site[—(P,S)═O][—NHR^(E), —OH], wherein R^(E) is an electron-withdrawinggroup; wherein the organic compound to be oxidized is selected from thegroup consisting of x^(s)R^(X) _(n), R^(s1)R^(s2)C═CR^(s3)R^(s4) andR^(s1)R^(s2)CH—(C═O)R^(s3); wherein: X^(s) is selected from the groupconsisting of S, Se, P and N; R^(X) is the same or different on X and isselected from the group consisting of (a) —NR^(Y) ₂, (b) —SR^(Y), (c)—OR^(Y), (d) —OSiR^(y) ₃, (e) C₁ to C₂₀ straight chain, branched chainor cyclic aliphatic hydrocarbons, optionally having one or moreunsaturated bonds, (f) C₃-C₈-heterocycloalkyl and (g) C₆ to C₂₀ aromatichydrocarbon and partially arene-hydrogenated forms, wherein each of(e)-(g) is optionally substituted by one or more groups selected fromthe group consisting of (i) C₁ to C₂₀ straight chain, branched chain orcyclic aliphatic hydrocarbons, optionally having one or more unsaturatedbonds, (ii) C₃-C₈-heterocycloalkyl, and (iii) C₆ to C₂₀ aromatichydrocarbon and partially arene-hydrogenated forms; n is 2 when X^(s) isS or Se; or n is 3 when X^(s) is P or N; R^(p), R^(Y) and R^(s1) toR^(s4) are independently selected from the group consisting of (a) C₁ toC₂₀ straight chain, branched chain or cyclic aliphatic hydrocarbons,optionally having one or more unsaturated bonds, (b)C₃-C₈-heterocycloalkyl and (c) C₆ to C₂₀ aromatic hydrocarbon andpartially arene-hydrogenated forms, wherein each of (a)-(c) isoptionally substituted by one or more groups selected from the groupconsisting of (i) C₁ to C₂₀ straight chain, branched chain or cyclicaliphatic hydrocarbons, optionally having one or more unsaturated bonds,(ii) C₃-C₈-heterocycloalkyl, and (iii) C₆ to C₂₀ aromatic hydrocarbonand partially arene-hydrogenated forms; or R′ is hydrogen or a radicalof the formula:

wherein aliphatic or aromatic in said formula is selected from the groupconsisting of (a) C₁ to C₂₀ straight chain, branched chain or cyclicaliphatic hydrocarbons, optionally having one or more unsaturated bonds,(b) C₃-C₈-heterocycloalkyl and (c) C₆ to C₂₀ aromatic hydrocarbon andpartially arene-hydrogenated forms, wherein each of (a)-(c) isoptionally substituted by one or more groups selected from the groupconsisting of (i) C₁ to C₂₀ straight chain, branched chain or cyclicaliphatic hydrocarbons, optionally having one or more unsaturated bonds,(ii) C₃-C₈-heterocycloalkyl, and (iii) C₆ to C₂₀ aromatic hydrocarbonand partially arene-hydrogenated forms; wherein said imidodiphosphateshave the formula (I):

wherein: X and Y are, independently from each other, the same ordifferent and represent O, S, Se or NR^(N); Z¹ to Z⁴ are, independentlyfrom each other, the same or different and represent O, S or NR^(N); nstands for 0 or 1; W is a substituent being capable of forming acovalent or ionic bond with the imidodiphosphate moiety; R¹ to R⁴ are,independently from each other, the same or different and are eachselected from the group consisting of aliphatic, heteroaliphatic,aromatic and heteroaromatic groups, each of which groups is optionallyfurther substituted by one or more metal-free heterosubstituents,aliphatic, heteroaliphatic, aromatic or heteroaromatic groups, wherebyR¹ and R² form a ring system with P and, if present, Z¹ and Z², and R³and R⁴ form a ring system with P and, if present, Z³ and Z⁴,respectively; and R^(N) is selected from the group consisting of (a)hydrogen, (b) C₁ to C₂₀ straight chain, branched chain or cyclicaliphatic hydrocarbons, optionally having one or more unsaturated bonds,(c) C₃-C₈-heterocycloalkyl and (d) C₆ to C₂₀ aromatic hydrocarbon andpartially arene-hydrogenated forms, wherein each of (b)-(d) isoptionally substituted by one or more groups selected from the groupconsisting of (i) C₁ to C₂₀ straight chain, branched chain or cyclicaliphatic hydrocarbons, optionally having one or more unsaturated bonds,(ii) C₃-C₈-heterocycloalkyl, and (iii) C₆ to C₂₀ aromatic hydrocarbonand partially arene-hydrogenated forms; and tautomeric and ionic formsof said imidodiphosphates.
 2. The process according to claim 1, whereinthe imidodiphosphate of formula (I) is represented by formula (IV):

wherein in said formula (IV), the substituent R is the same or differenton each position and is a metal-free heterosubstituent or R^(N).
 3. Theprocess according to claim 2, wherein the chiral imidodiphosphate offormula (IV) has the following formula (IVa):

wherein the substituents R are different or optionally the same on eachposition, or its tautomeric or ionic form.
 4. The process according toclaim 1, wherein the chiral catalyst used is the chiralimidodiphosphate, and the chiral imidodiphosphate has the formula (II):


5. The process according to claim 4, wherein the chiral imidodiphosphateof formula (II) has at least one moiety:

that is a five to ten-membered ring structure.
 6. The process accordingto claim 4, wherein the chiral catalyst used is the chiralimidodiphosphate, and the chiral imidodiphosphate has the formula (III):


7. The process according to claim 6, wherein, in such formula (III), R¹to R⁴, respectively are each selected from the group consisting of (a)C₁ to C₂₀ straight chain, branched chain or cyclic aliphatichydrocarbons, optionally having one or more unsaturated bonds, (b)C₃-C₈-heterocycloalkyl and (c) C₆ to C₂₀ aromatic hydrocarbon andpartially arene-hydrogenated forms, wherein each of (a)-(c) isoptionally substituted by one or more groups selected from the groupconsisting of (i) C₁ to C₂₀ straight chain, branched chain or cyclicaliphatic hydrocarbons, optionally having one or more unsaturated bonds,(ii) C₃-C₈-heterocycloalkyl and (iii) C₆ to C₂₀ aromatic hydrocarbon andpartially arene-hydrogenated forms; and W is selected from the groupconsisting of (a) hydrogen, (b) —OH, (c) halogen, (d) a metal, (e) acationic organic group, (f) R^(w) and (g) a substituted silicon—SiR^(I)R^(II)R^(III), wherein R^(w), R^(I), R^(II) and R^(III) are thesame or different and each is selected from the group consisting of (i)hydrogen, (ii) halogen, (iii) C₁ to C₂₀ straight chain, branched chainor cyclic aliphatic hydrocarbons, optionally having one or moreunsaturated bonds, (iv) C₃-C₈-heterocycloalkyl and (v) C₆ to C₂₀aromatic hydrocarbon and partially arene-hydrogenated forms, whereineach of (iii)-(v) is optionally substituted by one or more groupsselected from the group consisting of (1) C₁ to C₂₀ straight chain,branched chain or cyclic aliphatic hydrocarbons, optionally having oneor more unsaturated bonds, (2) C₃-C₈-heterocycloalkyl and (3) C₆ to C₂₀aromatic hydrocarbon and partially arene-hydrogenated forms thereof; andits tautomeric and ionic forms.
 8. The process according to claim 6,wherein, in such formula (III), (R¹ and R²) and (R³ and R⁴),respectively each form a ring structure which is the same or differentand is derived from a bridged, optionally dimeric, aromatic structure,or a partially arene-hydrogenated form of such aromatic ring structure,each of said rings systems optionally being substituted by one or moresubstituents which are the same or different on each position and areeach selected from the group consisting of (a) hydrogen, (b) metal-freeheterosubstituents, (c) C₁ to C₂₀ straight chain, branched chain orcyclic aliphatic hydrocarbons, optionally having one or more unsaturatedbonds, (d) C₃-C₈-heterocycloalkyl and (e) C₆ to C₂₀ aromatic hydrocarbonand partially arene-hydrogenated forms, wherein each of (c)-(e) isoptionally substituted by one or more groups selected from the groupconsisting of (i) C₁ to C₂₀ straight chain, branched chain or cyclicaliphatic hydrocarbons, optionally having one or more unsaturated bonds,(ii) C₃-C₈-heterocycloalkyl and (iii) C₆ to C₂₀ aromatic hydrocarbon andpartially arene-hydrogenated forms; and its tautomeric and ionic forms.9. The process according to claim 1, wherein at least one of said ringstructures formed by (R¹ and R²) or (R³ and R⁴) is chiral, optionallywith a C₂ symmetry axis.
 10. The process according to claim 1, whereinthe ring structures formed by (R¹ and R²) and (R³ and R⁴), respectively,are identical.
 11. The process according to claim 1, wherein the organiccompound is enantioselectively oxidized with a peroxide compound in thepresence of a chiral imidodiphosphate catalyst, said imidodiphosphatehaving the formula (I).
 12. The process according to claim 1, wherein,in the formula (I), W represents hydrogen.
 13. The process according toclaim 1, wherein the organic compound has the formula X^(S)R^(X) _(n),wherein X^(S) represents S; n represents 2; and R^(X) is selected fromthe group consisting of (a) C₁ to C₂₀ straight chain, branched chain orcyclic aliphatic hydrocarbons, optionally having one or more unsaturatedbonds, (b) C₃-C₈-heterocycloalkyl and (c) C₆ to C₂₀ aromatic hydrocarbonand partially arene-hydrogenated forms, wherein each of (a)-(c) isoptionally substituted by one or more groups selected from (i) C₁ to C₂₀straight chain, branched chain or cyclic aliphatic hydrocarbons,optionally having one or more unsaturated bonds, (ii)C₃-C₈-heterocycloalkyl, and (iii) C₆ to C₂₀ aromatic hydrocarbon andpartially arene-hydrogenated forms.
 14. The process according to claim1, wherein the peroxide R^(p)—OOH is selected from the group consistingof (a) hydrogen peroxide, (b) aliphatic or aromatic hydroperoxide, (c)aliphatic or aromatic percarboxylic acid and (d) mixtures thereof.
 15. Aprocess for the asymmetric oxidation of an organic compound, saidprocess comprising reacting the organic compound with at least oneperoxide compound R^(p)—OOH in the presence of a chiral catalyst;wherein the at least one peroxide compound is activated in favor of saidreacting by hydrogen bonding of the at least one peroxide compound tosaid chiral catalyst; wherein said organic compound is selected from thegroup consisting of organic compounds of the formulae X^(s)R^(X) _(n),R^(s1)R^(s2)C═CR^(s3)R^(s4) and R^(s1)R^(s2)CH—(C═O)R^(s3); wherein:X^(s) is selected from the group consisting of S, Se, P and N; R^(X) isthe same or different on X and is selected from the group consisting of(a) —NR^(Y) ₂, (b) —SR^(Y), (c) —OR^(Y), (d) —OSiR^(y) ₃, (e) C₁ to C₂₀straight chain, branched chain or cyclic aliphatic hydrocarbons,optionally having one or more unsaturated bonds, (f)C₃-C₈-heterocycloalkyl and (g) C₆ to C₂₀ aromatic hydrocarbon andpartially arene-hydrogenated forms, wherein each of (e)-(g) isoptionally substituted by one or more groups selected from the groupconsisting of (i) C₁ to C₂₀ straight chain, branched chain or cyclicaliphatic hydrocarbons, optionally having one or more unsaturated bonds,(ii) C₃-C₈-heterocycloalkyl, and (iii) C₆ to C₂₀ aromatic hydrocarbonand partially arene-hydrogenated forms; n is 2 when X^(s) is S or Se; orn is 3 when X^(s) is P or N; R^(p), R^(Y) and R^(s1) to R^(s4) areindependently selected from the group consisting of (a) C₁ to C₂₀straight chain, branched chain or cyclic aliphatic hydrocarbons,optionally having one or more unsaturated bonds, (b)C₃-C₈-heterocycloalkyl and (c) C₆ to C₂₀ aromatic hydrocarbon andpartially arene-hydrogenated forms, wherein each of (a)-(c) isoptionally substituted by one or more groups selected from the groupconsisting of (i) C₁ to C₂₀ straight chain, branched chain or cyclicaliphatic hydrocarbons, optionally having one or more unsaturated bonds,(ii) C₃-C₈-heterocycloalkyl, and (iii) C₆ to C₂₀ aromatic hydrocarbonand partially arene-hydrogenated forms; or R^(p) is hydrogen or aradical of the formula:

wherein aliphatic or aromatic in said formula is selected from the groupconsisting of (a) C₁ to C₂₀ straight chain, branched chain or cyclicaliphatic hydrocarbons, optionally having one or more unsaturated bonds,(b) C₃-C₈-heterocycloalkyl and (c) C₆ to C₂₀ aromatic hydrocarbon andpartially arene-hydrogenated forms, wherein each of (a)-(c) isoptionally substituted by one or more groups selected from the groupconsisting of (i) C₁ to C₂₀ straight chain, branched chain or cyclicaliphatic hydrocarbons, optionally having one or more unsaturated bonds,(ii) C₃-C₈-heterocycloalkyl, and (iii) C₆ to C₂₀ aromatic hydrocarbonand partially arene-hydrogenated forms; wherein said chiral catalyst isselected from the group consisting of chiral compounds (a) and (b),wherein the chiral compounds (a) are selected from the group consistingof chiral imidodiphosphates, and the chiral compounds (b) are selectedfrom the group consisting of phosphoric acids, sulfonic acids,bisulfonimides, triflyl phosphoramides, and phosphinyl phosphoramides,said chiral compounds (b) comprising a catalytically active site[—(P,S)═O][—NHR^(E), —OH], wherein R^(E) is an electron-withdrawinggroup; and wherein said imidodiphosphates have the formula (I):

wherein: X and Y are, independently from each other, the same ordifferent and represent O, S, Se or NR^(N); Z¹ to Z⁴ are, independentlyfrom each other, the same or different and represent O, S or NR^(N); nstands for 0 or 1; W is a substituent being capable of forming acovalent or ionic bond with the imidodiphosphate moiety; R¹ to R⁴ are,independently from each other, the same or different and are eachselected from the group consisting of aliphatic, heteroaliphatic,aromatic and heteroaromatic groups, each of which groups is optionallyfurther substituted by one or more metal-free heterosubstituents,aliphatic, heteroaliphatic, aromatic or heteroaromatic groups, wherebyR¹ and R² form a ring system with P and, if present, Z¹ and Z², and R³and R⁴ form a ring system with P and, if present, Z³ and Z⁴,respectively; and R^(N) is selected from the group consisting of (a)hydrogen, (b) C₁ to C₂₀ straight chain, branched chain or cyclicaliphatic hydrocarbons, optionally having one or more unsaturated bonds,(c) C₃-C₈-heterocycloalkyl and (d) C₆ to C₂₀ aromatic hydrocarbon andpartially arene-hydrogenated forms, wherein each of (b)-(d) isoptionally substituted by one or more groups selected from the groupconsisting of (i) C₁ to C₂₀ straight chain, branched chain or cyclicaliphatic hydrocarbons, optionally having one or more unsaturated bonds,(ii) C₃-C₈-heterocycloalkyl, and (iii) C₆ to C₂₀ aromatic hydrocarbonand partially arene-hydrogenated forms; and tautomeric and ionic formsof said imidodiphosphates.